The normal functioning of biological systems requires, inter alia, proper balance between formation and elimination of damaging substances. Oxidative stress, for example, represents an imbalance between the levels of damaging oxidizing species, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), in a biological system and the insufficient ability of that biological system to readily neutralize or eliminate the oxidizing species. Consequences of this stress include but are not limited to deleterious modification to cellular proteins, lipids and DNA.
Oxidative stress is associated with a wide range of diseases and other medical conditions, including for example Alzheimer's disease, Parkinson's disease, diabetes and pathologies secondary to diabetes, rheumatoid arthritis, neurodegeneration (particularly in motor neuron diseases), airway inflammation and hyper-responsiveness (for example, asthma), and some skin disorders, such as vitiligo.
In some of these cases, it is unclear whether the oxidative stress is the cause or the consequence of the medical condition. However, in many cases, lowering the oxidative stress leads to improvement in the disease manifestation. In many other cases, lowering the oxidative stress may prevent the disease outbreak. In addition to pathological conditions, oxidative stress is also known to be involved in some undesired components of aging.
Thiol (—SH) containing compounds are a type of molecules capable of neutralizing several types of damaging oxidative species, thus acting as reducing reagents. The activity of this group of compounds is mainly due to the sulfur atom they comprise which participates in nucleophilic attack on toxic electrophiles, scavenging free radicals, effecting repair of damaged targets through hydrogen atom donation, altering the redox status of the cell, or affecting gene transcription or protein function.
Thiol containing compounds include natural molecules, produced by all living organisms including animals and plants, as well as synthetic molecules. Examples of natural thiol containing antioxidants include glutathione, which is one of the most potent and important antioxidants in mammals, thioredoxins and cysteine.
Examples of synthetic thiol containing redox molecules include N-acetylcysteine amide, as described, for example, in Atlas et al., (2005) Free Radic Biol Med, Vol. 38(1), pp. 136-45. Another example is N-acetyl-cysteine-proline-cysteine-amide (CB3), described, for example, in Kim et al. (2011) 183(8):1015, which evaluated its protective properties in allergic airway diseases using an ovalbumin (OVA)-inhalation model in mice.
U.S. Pat. No. 5,874,468 discloses brain targeted low molecular weight, hydrophobic antioxidants and use of antioxidants in treatment of central nervous system neurodegenerative disorders such as Parkinson's, Alzheimer's and Creutzfeldt-Jakob's diseases and in treatment of conditions of peripheral tissues, such as acute respiratory distress syndrome, amyotrophic lateral sclerosis, atherosclerotic cardiovascular disease and multiple organ dysfunction, in which oxidants are overproduced.
U.S. Pat. No. 6,369,106 discloses a method of reducing oxidative stress in the brain of an organism having a blood brain barrier and suffering an ischemic brain injury, the method comprising the step of administering a compound to the organism, the compound having (a) a combination of molecular weight and membrane miscibility properties for permitting the compound to cross the blood brain barrier of the organism; (b) a readily oxidizable chemical group for exerting antioxidation properties; and (c) a chemical make-up for permitting the compound or its intracellular derivative to accumulate within the cytoplasm of cells.
International Patent Application Publication No. WO 2002/034202 discloses an antioxidant compound characterized by (a) a peptide including at least three amino acid residues of which at least two are cysteine residues, each having a readily oxidizable sulfhydryl group for effecting antioxidation; and at least two peptide bonds, each being cleavable by at least one intracellular peptidase; and (b) a first hydrophobic or non-charged moiety being attached to an amino terminal of the peptide via a first bond and a second hydrophobic or non-charged moiety being attached to a carboxy terminal of the peptide via a second bond, the first hydrophobic or non-charged moiety and the second hydrophobic or non-charged moiety are selected so as to provide the antioxidant compound with membrane miscibility properties for permitting the antioxidant compound to cross cellular membranes; wherein cleavage of the at least two peptide bonds by the at least one intracellular peptidase results in generation of a plurality of antioxidant species, each including one of the cysteine residues having the readily oxidizable sulfhydryl group and which is also active in effecting antioxidation, thereby providing for a plurality of different antioxidant species acting in synergy in exerting antioxidation.
Metal chelation is another important aspect in protecting biological systems from harmful substances. Metals, particularly heavy metals, are known to exert toxic effects when present in inappropriate amounts. Metal ions may generate free radicals reactions, thereby contributing to oxidative stress.
Ionizing radiation such as ultraviolet (UV) light, X rays, gamma rays, neutron beam and proton beam among others, may induce oxidative stress, inflammation, bone marrow damage (resulting in leukopenia, thrombocytopenia and anemia), digestive system damage (including loss of microvilli in the intestine walls) and abundant mutagenic and cytotoxic DNA lesions, which are responsible for the development of benign tumors, cancer (including hematological malignancies) and many other harmful conditions and disorders. Ionizing radiation promotes the production of free radicals, therefore antioxidants may protect against ionizing radiation-induced damage. It has been shown that antioxidant thiols (N-acetylcysteine amide, glutathione and thioproline) are capable of protecting against radiation-induced damage to cellular DNA in human blood lymphocytes (Tiwari et al. Mutat Res. 2009, 31;676(1-2):62-8). The various sources of natural ionizing radiation include cosmic radiation, solar radiation (including UV and protons) and high radon gas environments. The various sources of artificial ionizing radiation include external and internal radiation during medical procedures such as diagnostic imaging and scanning, injected or swallowed radioactive isotopes, nuclear medicine and radiation therapy, among others. There is an unmet need for improved compositions directed to the prevention and treatment of damages caused by ionizing radiation, suitable for oral, topical and systemic administration.
Additionally, there still remains a need for more effective means to handle conditions associated with excess amounts or excessive concentrations of damaging substances in cells. For example, it would be highly beneficial to have antioxidant, anti-inflammatory, anti-allergy and metal chelating compounds, with a combination of high potency, good stability, bioavailability and sufficient half life to achieve the desired effects.